Dr Nahid Aslani General Pediatrics Medical University Of Isfahan VITAMINS D Deficiency Dr Nahid Aslani General Pediatrics Medical University Of Isfahan

Vitamin Facts Organic substances that are essential in minute quantities to the nutrition of most animals and some plants, act especially as coenzymes in the regulation of metabolic processes but do not provide energy.

VITAMIN D DEFICIENCY

Vitamin D, a lipid-soluble vitamin and prohormone is known to play an important role in bone metabolism through regulation of calcium and phosphate homeostasis.

EPIDEMIOLOGY Vitamin D deficiency is a global health problem. With all the medical advances of the century, vitamin D deficiency is still epidemic. Over a billion people worldwide are vitamin D deficient or insufficient.

The high prevalence of hypovitaminosis D in a number of developing countries exists despite the fact that a large number of these countries lie in zones that have sufficient sunlight for vitamin D synthesis for most if not all of the year.

METABOLISM AND FORMS OF VITAMIN D Vitamin D is a prohormone that is synthesized in the skin after exposure to ultraviolet radiation. Less than 10 percent of vitamin D comes from dietary sources in the absence of food fortification or use of supplements.

METABOLISM AND FORMS OF VITAMIN D Cholecalciferol (vitamin D3) Ergocalciferol ( vitamin D2) Calcidiol (25-hydroxyvitamin D or 25[OH]D) Calcitriol (1,25-hydroxyvitamin D or 1,25[OH]2D)

Pathophysiology

CAUSES OF VITAMIN D DEFICIENCY Lack of vitamin D in the diet, often in conjunction with inadequate sun exposure . Inability to absorb vitamin D from the intestines . Inability to process vitamin D due to kidney or liver disease .

Skin pigmentation determines the duration of sun exposure necessary to achieve a certain concentration of vitamin D. MED (the amount of UV-B required to produce slight pinkness of the skin), exposure to the equivalent MED of whole-body UV-B results in similar vitamin D levels.

Exposure to sunlight During the spring, summer, and fall, 10 to 15 minutes of sun exposure between between 1000 to 1500 hours (10:00 AM and 3:00 PM) is sufficient for adequate vitamin D synthesis in light skinned individuals .

Sunscreen Sunscreen absorbs UV-B and some UV-A light and prevents it from reaching and entering the skin. A sun screen with a sun protection factor (SPF) of 8 can decrease vitamin D3 synthetic capacity by 95%, and SPF 15 can decrease it by 98% .

Latitude and Season In the winter months, the rays of the sun enter the atmosphere at an oblique angle, UV-B photons have to pass through a greater distance of the atmosphere, and more UV-B photons are absorbed by ozone. Beyond a latitude of 40° and during winter, little or no UV-B radiation reaches the surface of the earth.

Exposure to the sun is not recommended as a source of vitamin D for infants and children due to the potential long-term risks of skin cancer

Other Causes Of Vitamin D Deficiency Poor Maternal Vitamin D Status Prematurity Exclusive Breastfeeding Obesity Malabsorption(inflammatory bowel disease, CF, cholestasis) Medications

CLINICAL MANIFESTATIONS Rickets Osteomalacia Biochemical changes

Radiographic Scoring System of Wrist

Radiographic Scoring System of Knee

Current Researches Immunological conditions Multiple Sclerosis Type 1 diabetes Inflammatory bowel disease Childhood Asthma and AD Mood disorders Cardiovascular disease Cancers(breast, prostate, and colon)

Current Researches Hypertension Hyperglycemia The metabolic syndrome Respiratory infections

VITAMIN D SUPPLEMENTATION

Breast and Formula Fed Infants Vitamin D content of breast milk is low (15 to 50 IU/L) Infant formulas usually providing at least 400 IU/L.

American Academy of Pediatrics, November 2012 A supplement of 400 IU per day of vitamin D is recommended for all breastfed infants and children beginning in the first few days of life

American Academy of Pediatrics, July , 2015 Maternal vitamin D supplementation with 6400 IU/day safely supplies breast milk with adequate vitamin D to satisfy her nursing infant’s requirement and offers an alternate strategy to direct infant supplementation.

AAP new guidelines for preterm infants For babies that weigh less than 1500 g , they should get biochemical testing for bone mineral status starting 4 to 5 weeks after birth. If the babies’ serum alkaline phosphatase activity is greater than 800 IU/L to 1000 IU/L or the baby is getting fractures, they should receive radiographic evaluation for rickets and treated with calcium and phosphorus as necessary.

Guidelines for preterm infants For preterm and very low birth weight infants that weigh less than 1500 g, they should get 200 to 400 IU of vitamin D/day. For infants that weigh over 1500 g, they should get 400 IU/day.

OTHER AGE GROUPS Healthy children 1 to 18 years of age – 600 International Units (15 micrograms) daily In pregnant and lactating women, the RDA for vitamin D is 600 int. units , which is the same as for women who are not pregnant .

2011 Pediatrics

Iranian Guideline for Vitamin D Supplementation 0-24 Month :400 IU /day from 3-5 days after birth. 2 -12 years: 800 IU/day (50,000 IU every 2 month) 12-70 years: 50,000 IU every 1 month. Above 70 years: 50.000 IU every 2 weeks.

SCREENING FOR VITAMIN D DEFICIENCY

SCREENING Exclusively breastfed or premature infants Infants and young children with nonspecific symptoms such as poor growth, gross motor delays, irritability . Dark-skinned infants and children Children on anticonvulsants or chronic glucocorticoids Children with chronic diseases Children with low dietary intake of vitamin D Obesity, amenorrhea, immobilization, chronic kidney or liver disease.

MEASUREMENT 25(OH)D is the major circulating form of vitamin D with a half-life of 2-3 weeks and its levels are the best available indicators of vitamin D status. Although 1, 25 (OH)2D (calcitriol) is the active form, it has a half-life of only 4 hours and it is not a good indicator of vitamin D stores .

SCREENING Serum ALP if elevated for age (500 IU/L in neonates and 1000 IU/L in children up to 9 years of age All children with radiographic evidence of rickets have low vitamin D levels, not all have high ALP levels, and the wrist radiograph may be the most reliable test for detecting subclinical rickets.

GOLD STANDARD vitamin D ASSAY High performance liquid chromatography (HPLC) liquid chromatography-mass spectroscopy (LC-MS) Radioimmunoassays also perform well enough for clinical use

MEASUREMENT Significant controversy has been associated with determining standards of vitamin D sufficiency, insufficiency, and deficiency.

2016 Global Consensus recommendations Vitamin D sufficiency: 20 to 100 ng/mL (50 to 250 nmol/L) Vitamin D insufficiency: 12 to 20 ng/mL (30 to 50 nmol/L) Vitamin D deficiency: <12 ng/mL (<30 nmol/L)

Biochemical changes

TREATMENT Vitamin D replacement therapy is necessary for : children presenting with low vitamin D levels (25(OH)D <20 ng/mL (50 nmol/L)) Rickets.

Endocrine Society Guideline Infants <12 months old: 2000 IU/day for six to twelve weeks, followed by maintenance dosing of at least 400 IU/day. Children >12 months old: 2000 IU/day for six to twelve weeks, or 50,000 IU per week for six weeks , followed by maintenance dosing of 600 to 1000 IU/day.

Infants <1 month old 1000 IU/day for six weeks, followed by maintenance dosing of at least 400 IU/day. Infants 1 to 12 months old 1000 to 2000 IU/day for six weeks, followed by maintenance dosing of at least 400 IU/day. Children >12 months old 2000 IU/day for six weeks, or 50,000 IU per week for six weeks , followed by maintenance dosing of 600 to 1000 IU/day.

Global Consensus Recommendations Infants ≤12 months old: 2000 IU/day for three months , followed by maintenance dosing of 400 IU/day. Children >12 months to 12 years old: 3000 to 6000 IU/day for three months, followed by maintenance dosing of 600 IU/day. Children >12 years old: 6000 IU/day for three months, followed by maintenance dosing of 600 IU/day.

Children with obesity, malabsorptive diseases, or those on medications that impact vitamin D metabolism may require higher replacement doses (two to three times higher than in children without these conditions), followed by higher maintenance dosing .

“stoss” therapy Short-term administration of high dose vitamin D, known as “stoss therapy”, is an effective alternative. A single dose of 600,000 int. units of vitamin D as an intramuscular injection is an excellent solution for persistent non-compliance.

Calcitriol (1,25(OH)2D) Is not necessary, except in conditions of severe vitamin D deficiency with severe symptomatic hypocalcemia. Dose of 20 to 100 ng/kg/day with intravenous calcium gluconate and high doses of vitamin D may normalize plasma calcium levels more rapidly than standard vitamin D treatment( no role in building up vitamin D stores).

Calcium supplementation Hypocalcemia should be treated with calcium supplements at a dose of 10 to 20 mg/kg of elemental (1 to 2 mL/kg of 10 percent calcium gluconate) Calcium replacement at doses of 30 to 75 mg/kg/day of elemental calcium given in two to three divided doses for two to four weeks, until vitamin D doses have been reduced to maintenance levels of 600 to 1000. Prevention of Nutritional Rickets include administration of a daily dose of 500 mg of elemental oral calcium.

2011 Pediatrics

Borderline vitamin D levels 25(OH)D between 12 and 20 ng/mL (30 to 50 nmol/L) Not usually give vitamin D replacement therapy unless there are other signs of vitamin D deficiency or important risk factors ( very low nutritional intake or perinatal risk factors) . Monitoring 25(OH)D levels in these children periodically, and initiating treatment if levels fall below 12 ng/mL (30 nmol/L).

Follow-up Patients with rickets. Patients without rickets but with low vitamin D levels and biochemical changes . Patients presenting with only low levels of vitamin D and no other biochemical changes or evidence of rickets.

Patients with rickets Radiographic healing , normalization of serum 25(OH)D, PTH, calcium and phosphorus levels, and long-term maintenance of vitamin D sufficiency. Complete radiologic healing may take months, but changes are evident in 1 week. A radiograph should also be repeated at 3 months.

Patients without rickets but with low vitamin D levels and biochemical changes Check serum 25(OH)D levels and other chemistries after six to eight weeks of high-dose therapy, then again after several months of maintenance therapy, then annually thereafter.

Patients presenting with only low levels of vitamin D and no other biochemical changes or evidence of rickets Check 25(OH)D levels after two to three months, then as needed thereafter, depending on the adequacy of the patient's intake and adherence to maintenance supplements.

Vitamin D Excess Consuming too much vitamin D through diet alone is not likely unless you routinely consume large amounts of cod liver oil. It is much more likely to occur from high intakes of vitamin D in supplements.

EXCESS The recommended upper limits for long-term vitamin D intake are 1,000 IU for children <1 year old and 2,000 IU for older children and adults. Vitamin D intoxication has been documented in adults taking more than 60,000 international units per day.

Laboratory Findings Hypercalcemia Extremely elevated levels of 25-D (>150ng/mL) Hyperphosphatemia PTH levels are appropriately decreased Nephrocalcinosis

Clinical Manifestations Symptoms of acute intoxication are due to hypercalcemia and include confusion, polyuria, polydipsia, anorexia, vomiting, and muscle weakness. Chronic intoxication may cause nephrocalcinosis, bone demineralization and pain.

Treatment The treatment of vitamin D intoxication focuses on control of hypercalcemia. The mainstay of the initial treatment is aggressive therapy with normal saline, often in conjunction with a loop diuretic to further increase calcium excretion.

Treatment Glucocorticoids Calcitonin Bisphosphonates Hemodialysis Additional sources of vitamin D such as multivitamins and fortified foods should be eliminated or reduced.